1. Field of the Invention
The present invention relates to a novel aldose reductase inhibitor and a method for producing the same.
The novel compound of the invention is represented by the formula: ##STR3## wherein X is methylene or carbonyl;
R is ##STR4## R.sup.1, R.sup.2, R.sup.3, and R.sup.4 each is hydrogen or lower alkyl. PA1 R is ##STR6## R.sup.1, R.sup.2, R.sup.3, and R.sup.4 each is hydrogen or lower alkyl, or the salt thereof, PA1 preferably to the compound wherein R is ##STR7## where X is methylene; PA1 R is ##STR8## where X is carbonyl, or the salt thereof, PA1 and more preferably to the compound wherein R.sup.3 or R.sup.4 is hydrogen or the salt thereof. PA1 R is ##STR11## where X is carbonyl; isolating the above mentioned compound from the cultured medium and optionally alkylating the compound. It further provides a pharmaceutical agent comprising the compound, as an effective ingredient, in association with a pharmaceutically acceptable, substantially nontoxic carrier or excipient, which inhibits an aldose reductase.
2. Description of the Prior Art
The incidence rate of diabetes has hitherto increased and various complications thereof have become a quite serious problem. The complications of diabetes may be caused by, for example, accumulation of polyol (e.g., sorbitol), free radical peroxidation, and glycosylation of proteins at the site of lysine residues. An inhibitor for aldose reductase (abbreviated hereinafter as AR) relating to polyol accumulation is expected to serve as a medicine for diabetic complications, that is, diseases arising from diabetes such as diabetic neuropathy, diabetic cataract, diabetic keratopathy, diabetic retinopathy, and diabetic nephropathy. Although there have been many investigations into the development of such a medicine, development of more beneficial inhibitors is still necessary (see Reinhard Sages, Advances in Drug Research, 18, 139-175 (1989)). Typical examples of AR inhibitors include Quercitrin reported by Horhammer et al. (see Arch Pharm., 292, 113 (1959)).
It has been revealed that AR as a rate-limiting enzyme in the metabolic pathway of polyol is present in blood vessels, peripheral nerves, lenses, retinae, and so forth, in which many complications of diabetes often occur. Therefore, the significance of AR became understood in relation to diabetes. In the state of glycophilia such as diabetes, a larger amount of glucose than is capable of being metabolized in the glycolysis system is present in cells and the metabolism of glucose in the metabolic pathway of polyol can readily be promoted because glucose is used as a substrate for AR. As a result, the abnormal accumulation of sorbitol is further enhanced. Sorbitol is a relatively stable substance; once the cells produce sorbitol, very little extracellular release of the sorbitol is found. The imbalance between the production and metabolism causes the intracellular accumulation of this sugar alcohol. This results in an increase in intracellular osmotic pressure and a lot of water remains in the cells, thereby making it impossible to maintain the normal function of the cells and exhibiting a disorder of the cells. If the AR activity is inhibited, the abnormal intracellular accumulation of sorbitol can be avoided, and there is a great possibility that the normal function of the cells can be maintained. Accordingly, the present inventors have made an effort to search compounds having an AR-inhibiting activity.